Tuesday, July 25, 2017

Metformin (01) Insulin

They are using BB/S rats which spontaneously develop T1DM if fed standard rodent chow. In the absence of exogenous insulin they die but giving them a little Ultratard twice daily keeps them alive for quite some time. Stopping the Ultratard allows exogenous insulin withdrawal to produce an acute, alive, an-insulinaemic rodent model. This is the model used and at the start of this experiment the rats had no detectable insulin in their blood.

At time point -60 these an-insulinaemic rats were given metformin intrajejunally. Over the next 60 minutes the metformin did nothing to lower plasma glucose. At time point zero they were given a small intravenous bolus of glucose. Metformin had no effect on the additional hyperglycaemia induced.

At time point +90 they were given neutral insulin intravenously. In the control group plasma glucose concentration dropped to a nadir of 20mmol/l at time point +150 but in the metformin treated rats the same dose of insulin continued to reduce the plasma glucose to 10mmol/l at time point +180, when p dropped below 0.05.

So.

Insulin is essential to demonstrate any effect of metformin on blood glucose.

Any idea about how metformin works, be that via the inhibition of mtG3Pdh or via inhibition of complex I, has to accommodate the essentiality of insulin.

7 comments:

Hi Peter, great to see a post about one of my fav topics - metformin ;p

I'm not particularly s urprised. A primary mechanism of metformin (it has so many) is considered to be GLP-1 augmentation. GLP-1 itself has many effects but major one is to orchestrate insulin release with rising glucose. This "fact" has been exploited by dishonest insulin denialists such as stephan guyenet to evidence his nonsense idea that insulin is slimming, lol (as GLP-1 , incretin augmenting substances such as metformin are also associated with wt loss, but have an early insulin boosting effect). In reality while GLP-1 agents promote healthy insulin release to rising glucose which is absolutely physiologically normal and generally breaks in metabolic disorder, there is a much more relevant (to wt loss) total reduction of circulating insulin absolutely due to constrained gluconeogenesis from the liver, as well as generalized anorexia and spontaneous reduced food intake through serotonin signalling in the brain. But thats kind of a tangent (how stupid/dishonest stephan is...)

Metformin is not really therapeutically potent for acute glucose lowering effects (which is why its favored by physicians, incredibly safe almost no risk of hypoglycemia), but yes i would expect antihyperglycemic effects of an acute glucose bolus to be impaired in an aninsulinemic rodent even given metformin. GLP-1 stimulated insulin release (healthy, normal) is a big part of how metformin works at least when dealing with acute rises of blood sugar from meals.For longer term/over all blood sugar benefits, fasting hyperglycemia, ect metformin likely works through improvements of fat burning, decreased liver gluconeogenesis, and so on.

Several more parts to go on this thread. The other concept to me is that metformin, which blocks mtG3Pdh actually improves insulin sensitivity... When mtG3Pdh is essential for insulin action. Not sure how long the thread will be but I started with (01) rather than (1). Dunno how it will develop, but there is logic to it!

DVS - metformin absolutely enhanced ketosis for me, IMO the most prominent effect is hepatic gluconeogenesis inhibition. Mu agonists which also inhibit liver glucose/enhance glucose uptake also normalize ketosis for me. For background I am very keto resistant which i attribute to massive wt loss (i.e. body easily wants to stop burning fat, one aspect of this low leptin is abnormal glucose production from liver that assists with higher insulin responses and inhibition of lipolysis therebyz). The agents that most dramatically normalize i.e. raise my ketones are agents that correct liver glucose excess.

My feeling is that it will help people like Wooo who are exquisitely insulin sensitive, having post-disteneded, currently-shrunken adipocytes. Anything you can do to decrease insulin signalling will limit fat storage and if you block mtG3Pdh you will only induce insulin signalling using ETFdh (plus complex II of course) to drive RET and generate that superoxide to initiate insulin signalling by oxidising (saturated) fat. At the moment I'm more interested in the opposite situation where much larger fluxes of RET generate insulin resisting levels of superoxide...

About Me

I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory.
I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Organisation (or lack of it)!

The "labels" function on this blog has been used to function as an index and I've tended to group similar subjects together by using labels starting with identical text. If they're numbered within a similar label, start with (1). The archive is predominantly to show the posts I've put up in the last month, if people want to keep track of recent goings on. I might change it to the previous week if I ever get to time to put up enough posts in a week to justify it. That seems to be the best I can do within the limits of this blogging software!